Investigators/Authors: Martin McKeown,MD., Silke Appel-Cresswell,MD, University of British Columbia

Objectives: Investigate whether changes in the shape rather than the overall volume of basal ganglia structures represent an early and sensitive marker for the development of motor and non-motor symptoms in PD.

Background: Functional neuroimaging, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) have been suggested as biomarkers in PD. While they have proved valuable in examining some aspects of the rate of progression of the disease, their use as sensitive biomarkers has not been definitively established. Microglial activation assessed with 11C-(R)-PK95111 is a potential candidate as a biomarker, but two published studies show discrepancies between activation seen in the midbrain and striatum. Impaired cardiac uptake of 123I-MIBG, suggesting sympathetic involvement in PD, has been suggested as an early biomarker in PD. Metabolomic profiling, where many (>1,000) metabolites are probed for characteristics of disease are promising, but it is difficult to separate the core features of the disease with other changes in metabolites due to inter-subject variation and the effects of treatment. Thus unfortunately, for a variety of reasons, ranging from poor sensitivity and specificity, to difficulty in widely disseminating the technology, all biomarkers proposed thus far have not yet developed into clinically useful tools for a broad range of patients. Accurate and widely available biomarkers for early disease remain an elusive goal. While investigators pilot data give them reason to believe that the proposed methods have the potential to predict, in prospective fashion, upcoming deficits, and that these measurements are more sensitive than currently employed techniques such as diffusion tensor imaging and cortical thickness measurements, the purpose of this proposal is the initial validation of these MRI biomarker(s), a necessary first step of the “cascade of processes, each adding confidence to the initial candidate biomarker” necessary for full biomarker validation.

Methods/Design: Investigators will recruit 70 mild-moderate PD subjects, and 30 age and gender-matched healthy controls. Subjects will undergo: clinical assessment consisting of motor evaluation (UPDRS), a battery of neuropsychiatric scales, diagnostic interview and cognitive assessment, as well as balance assessment with a trained physiotherapist, and MRI scanning with a 3T scanner. Using a specialized multidisciplinary team, investigators will compare the MRI results with UPDRS motor scores and clinical measures.

Relevance to Diagnosis/Treatment of Parkinson’s disease: This study will lay the groundwork for further studies that could longitudinally assess the predictive value of the proposed MRI measurements for the development of clinical deficits.

September 2013 Project Update:

The investigators to date have evaluated 45 subjects and have requested a no-cost extension to complete recruitment and evaluation, which they anticipate completing without exceeding the original grant budget.

The investigators have developed and deployed algorithms for the evaluation of the MRI data, which is expected will contribute to increased test-retest accuracy and was one of the goals of the project.

Using this automation, the data collected so far has supported the hypothesis that the shape of basal ganglia structures do in fact predict the presence or absence of the symptoms of Parkinson’s disease. As hypothesized, structure volume was not predictive of symptom expression.

The investigators further considered the possibility of correlating these shape parameters with severity of Parkinson’s symptoms. To date, while there are indications that this may result in a positive finding, the number of subjects analyzed has not yielded the statistical power to support a definitive answer. It is hoped that additional data collection will support the trends observed to date and will thus support this hypothesis, as well.

Results/Conclusions: This study is not yet complete. Findings to-date support the hypothesis that neurodegeneration has a greater impact on the shape of deep brain structures than their volume. It is hoped that, at the end of the study, the finding that severity of disease will also correlate with shape changes. Findings to-date suggest the possibility that longitudinal imaging could provide deeper insight and should be considered as a follow-up study: shape change over time could be illustrative. Given that the MRI imaging modality used in this study is generally a low-cost option commonly available in a community setting and many aspects of the analysis have been automated, it is possible that this study could provide insight for future clinical diagnostics.

September 2014 Project Update:

The study is complete. The processed MRI data was successfully analyzed to measure the shape characteristics of subcortical structures for the caudate, putamen, thalamus, and pallidum in the left and right hemispheres. The analysis method achieved a substantial reduction in the complexity of the problem, reducing the dimensionality of the challenge of describing the shape properties from 104 to between 10 and 45 dimensions. However, the results failed to correlate with most clinical characteristics. Only tremor and a measure of anosmia (measured using the University of Pensylvania smell identification test or UPSIT) showed a significant correlation with the measurement of shape parameters. There is, however, the possibility, based on the UPSIT results, that the majority of the change in shape characteristics are occurring in the prodromal phase and this could offer new insight in that area.

Objectives: To identify risk factors as well as biological markers of early disease and revel information on the mode of conversion from asymptomatic to PD.

Background: About one third of the Ashkenazi Jewish patients with Parkinson's disease (PD) carry disease associated mutations in the LRRK2 gene. Recent studies from North African countries like Tunisia, Algeria and Morocco have reported that this mutation has been found also in the Arab population in a very high percentage. The age of the founder mutation (G2019S) in the LRRK2 gene among the Arabs of North Africa has been dated to about 5000 years ago while the age of the same mutation among the Ashkenazi Jews population is about 1300 years. The frequency of the G2019S mutation in the LRRK2 gene among Non-Ashkenazi Jews is unknown and neither are the clinical PD features of mutation carriers among those Sephardic Jews. Healthy, first degree relatives of patients with PD are at higher risk to develop PD. The exact risk is unknown but within the Ashkenazi population this risk ranges between 2-20 times higher than those healthy subjects with no family history of PD. With the current understanding that the pathological process in PD, within the brain and peripheral autonomic nervous system, begins 10-20 years prior to the appearance of motor symptoms, and with the increased interest in the development of sensitive biological markers for pre-motor diseased state in PD, there is a special interest in first degree relatives of PD patients as a population at risk which might develop the disease during their lives.

Methods/Design: One hundred PD patients who originated from countries around the Mediterranean Sea will be screened for the G2019S mutation in the LRRK2 gene. Patients with PD will be asked for permission to contact their families by mail. 100 healthy 1st degree relatives of those Sephardic PD patients and 50 healthy subjects with no history of PD in the family, who are over the age 35, will be invited to participate in a 5 years prospective clinical and genetic follow up study. Subjects interested in participation in the study will be invited to the MDU at TASMC for a yearly assessment

Relevance to Diagnosis/Treatment of Parkinson’s disease: Information on risk factors and biological markers of early disease might lead to better clinical counseling to subjects at risk about potential disease modifying measures as well as to the future development of protective therapeutic strategies in order to delay the appearance of motor symptoms.

September 2013 Project Update:

The investigators to date have recruited 75 healthy asymptomatic non-Ashkenazi first degree relatives of patients with PD to participate in the study. In addition, 10 non-Ashkenazi healthy age-matched subjects with no family history of PD were recruited to serve as the control group for this study. The cohort was constructed from 26 families each with one PD patients and one to four subjects from each family participated in the study. Three of the PD patients were found to have the LRRK2 G2019S mutation however none of the asymptomatic healthy relatives carried the mutation.

It is expected that the first degree relatives have a higher risk for developing PD than the control subjects, however there were no signs of PD in the cohort nor did they differ in their clinical evaluation from the controls. This is likely a result of the subjects’ age, which was considerably younger than the typical age at onset for their relatives with PD. In a post-hoc analysis, the investigators considered indicators that subjects were at risk of developing PD. Eight subjects were identified as at risk, all based on poor performance on the UPSID smell identification test. Five of those eight also showed signs of impaired cognition suggestive of bradyphrenia. No subjects had symptoms that met the prospective criteria for identifying parkinsonian features, however.

Results/Conclusions: This study is not yet complete. It is hoped that as the cohort is followed longitudinally, subtle symptoms can be identified prior to any subjects meeting the clinical diagnostic criteria for Parkinson’s disease and that these subtle features can inform the identification of a clinical evaluation protocol for risk of Parkinson’s.

September 2014 Project Update:

The investigators have continued to monitor the healthy relatives for signs of Parkinson’s disease through remote and in-clinic monitoring. No subjects have progressed to symptomatic Parkinson’s disease.

Objectives: Identify correlations between therapeutic choices and improved outcomes; Establish an evidence base as a foundation for future innovation; Improve the body of research to support evidence-based medicine decisions

Background: With an eye toward dramatically changing the quality of care in Parkinson’s disease, NPF launched the Quality Improvement Initiative (“NPF-QII”) in 2009. Committed to an evidence-based approach to quality improvement in care, NPF initiated this project to capture clinical interventions and patient-reported outcomes over time and from multiple centers across the U.S, Canada and internationally. Led by a steering committee of renowned movement disorders neurologists, NPF-QII is unique in its scope, in its capacity to leverage wide clinician participation and in its longitudinal data collection strategy. NPF-QII promises to accelerate clinical discovery, promote collaborative science and drive advancements in clinical practice toward true patient-centered care. Now in its third year, NPF-QII includes over 5,000 patients from 20 centers, with second-year data on 3,000 patients and third year data on almost 500. Over 12 abstracts have been presented at international scientific conferences and more than four papers have been published in specialized peer review journals. The scope and scale of this project is unprecedented in Parkinson’s disease, where no study of patients with a confirmed diagnosis of Parkinson’s disease has ever before been larger than 2,000 patients and no multi-year clinical study has included more than 1,000.

Methods: NPF-QII collects demographic data, information about the patient's Parkinson's disease and other comorbid illness, patient assessments of Parkinson's related physical, emotional and cognitive disability and clinician tests of mobility, memory and cognition. It also collects data on the burden of the disease on caregivers. Any person who receives medical care for the diagnosis of idiopathic Parkinson's disease at any of the participating Centers is eligible to participate in the Registry. There are no limitations for participation based on age, disease severity or presence of cognitive impairments. Registry data will be used to study the relationship between treatment and clinical symptoms of patients with Parkinson's.

Relevance to the diagnosis/treatment of PD: NPF’s Quality Improvement Initiative is building a body of evidence-based knowledge which will be used to drive improvements in the quality and consistency of care for all individuals diagnosed with Parkinson’s disease. In addition, data captured as part of this initiative will support comparative effectiveness research to identify the most effective and cost-effective ways to treat PD patients; identify positive health outcomes associated with various treatment approaches; encourage exploratory data analyses for the development of novel hypotheses for prospective clinical research; enable clinicians to track performance, and ultimately establish targeted metrics for excellent care, and most important, provide an unmatched framework to evaluate new treatments in real-world clinical settings.

September 2013 Project Update:

Over grant year 3 in this ongoing study, NPF-QII increased recruitment to 6722 and the total records collected to 12,394. Twenty NPF Centers of Excellence are participating in the study. In this year, NPF-QII achieved a number of key milestones.

Recruitment and retention. A major push to improve recruitment and retention in the study has been successful. Of the 18 centers that are active in the study (one of the centers has yet to start recruitment and a second center has withdrawn from the study), only two have recruitment below 200, the threshold for analysis. Now in its fourth year, loss to follow-up has been reduced to 9%, or approximately 4% per year of the study.

Scientific advances. New research has been published in the past grant year on the following topics:

Predictors of hospitalization: which symptoms most accurately predict hospitalization?

Depression treatment: which approach to depression care yield the best results?

Caregiver strain: which aspects of Parkinson’s disease are associated with the most severe strain on the family caregiver?

Later stage disease: what are the typical issues experienced by patients after 10 years with Parkinson’s?

Comorbidities: what are the common comorbidities associated with Parkinson’s disease and how do they interact with the Parkinson’s to affect patients’ health status?

Report to the community. In October 2012, NPF published a report on NPF-QII, introducing new branding for the study: the Parkinson’s Outcomes Project. This 24-page report, issued under the title: Parkinson’s Outcomes Project: Report to the Community, explained key developments in the Parkinson’s Outcomes Project. Sections in the report covered the impact of depression on patients, the importance of exercise, and how differences in care result in different outcomes across expert centers.

Results/Conclusions: This study is not complete. The key thread across grant year 3 has been depression: the importance of depression to patient outcomes was covered in the report at the beginning of the year while new research presented at the Movement Disorders Society meeting in June 2013 addressed which therapies changed outcomes. As the study is now identifying approaches that change outcomes, the next step for the study will be to build the electronic data collection tools and resources to help clinicians to apply these successful practices.

September 2014 Project Update:

Over grant year 4 in this ongoing study, NPF-QII increased recruitment to 7507 subjects and total records collected to 16,705. The University of Miami has joined the study and Mount Sinai School of Medicine in New York has stopped participation.

The study was recognized publicly through the award of the International Parkinson and Movement Disorders Society’s Young Investigator to Anhar Hassan, MD, of the Mayo Clinic in Rochester, MN. Dr. Hassan received one of three awards given at the June 2014 congress in Stockholm, Sweden and received the only award for clinical research. Dr. Hassan’s research was on the cohort of patients in NPF-QII who have survived over twenty years with Parkinson’s disease. The support of the Parkinson’s Unity Walk helped to make this possible.

To date, the NPF-QII study has provided data used in 24 conference presentations and 13 scientific papers through interpretation of results from 27 data analyses from collaboration among 53 scientific investigators. Over 150 neurologists have participated in the study.

Study results drew the attention of the national news media at the time of the death of actor Robin Williams. Early research from the study showed the importance of depression, and depression has been the focus of four papers from the study. Results from the study were mentioned in articles in Forbes, The Washington Post, Pharmacy Times, and The Detroit Free Press, among others.

Results: In addition to the above, the following papers have been published from the study over the grant period: